Angiogenesis inhibitors

ABSTRACT

The present invention relates to compounds which inhibit tyrosine kinase enzymes, compositions which contain tyrosine kinase inhibiting compounds and methods of using tyrosine kinase inhibitors to treat tyrosine kinase-dependent diseases/conditions such as angiogenesis, cancer, atherosclerosis, diabetic retinopathy or autoimmune diseases, in mammals.

This application is a 371 of PCT/US98/10590, filed on May 26, 1998.

BACKGROUND OF THE INVENTION

The present invention relates to compound which inhibit tyrosine kinaseenzymes, compositions which contain tyrosine kinase inhibiting compoundsand methods of using tyrosine kinase inhibitors to treat tyrosinekinase-dependent diseases/conditions such as neoangiogenesis, cancer,atherosclerosis, diabetic retinopathy or inflammatory diseases, inmammals.

Tyrosine kinases are a class of enzymes that catalyze the transfer ofthe terminal phosphate of adenosine triphospate to tyrosine residues inprotein substrates. Tyrosine kinases are believed, by way of substratephosphorylation, to play critical roles in signal transduction for anumber of cell functions. Though the exact mechanisms of signaltransduction is still unclear, tyrosine kinases have been shown to beimportant contributing factors in cell proliferation, carcinogenesis andcell differentiation. Accordingly, inhibitors of these tyrosine kinasesare useful for the prevention and treatment chemotherapy ofproliferative diseases dependent on these enzymes.

For example, a method of treatment described herein relates toneoangiogenesis. Neoangiogenesis occurs in conjunction with tumor growthand in certain diseases of the eye. It is characterized by excessiveactivity of vascular endothelial growth factor.

Vascular endothelial growth factor (VEGF) binds the high affinitymembrane-spanning tyrosine kinase receptors KDR and Flt-1. Cell cultureand gene knockout experiments indicate that each receptor contributes todifferent aspects of angiogenesis. KDR mediates the mitogenic functionof VEGF whereas Flt-1 appears to modulate non-mitogenic functions suchas those associated with cellular adhesion. Inhibiting KDR thusmodulates the level of mitogenic VEGF activity.

Vascular growth in the retina leads to visual degeneration culminatingin blindness. VEGF accounts for most of the angiogenic activity producedin or near the retina in diabetic retinopathy. Ocular VEGF mRNA andprotein are elevated by conditions such as retinal vein occlusion inprimates and decreased PO₂ levels in mice that lead toneovascularization. Intraocular injections of anti-VEGF monoclonalantibodies or VEGF receptor immunofusions inhibit ocularneovascularization in both primate and rodent models. Regardless of thecause of induction of VEGF in human diabetic retinopathy, inhibition ofocular VEGF is useful in treating the disease.

Expression of VEGF is also significantly increased in hypoxic regions ofanimal and human tumors adjacent to areas of necrosis. Monoclonalanti-VEGF antibodies inhibit the growth of human tumors in nude mice.Although these same tumor cells continue to express VEGF in culture, theantibodies do not-diminish their mitotic rate. Thus tumor-derived VEGFdoes not function as an autocrine mitogenic factor. Therefore, VEGFcontributes to tumor growth in vivo by promoting angiogenesis throughits paracrine vascular endothelial cell chemotactic and mitogenicactivities. These monoclonal antibodies also inhibit the growth oftypically less well vascularized human colon cancers in athymic mice anddecrease the number of tumors arising from inoculated cells. Viralexpression of a VEGF-binding construct of Flk-1, the mouse KDR receptorhomologue, truncated to eliminate the cytoplasmic tyrosine kinasedomains but retaining a membrane anchor, virtually abolishes the growthof a transplantable glioblastoma in mice presumably by the dominantnegative mechanism of heterodimer formation with membrane spanningendothelial cell VEGF receptors. Embryonic stem cells, which normallygrow as solid tumors in nude mice, do not produce detectable tumors ifboth VEGF alleles are knocked out. Taken together, these data indicatethe role of VEGF in the growth of solid tumors. Inhibition of KDR orFlt-1 is implicated in pathological neoangiogenesis, and these areuseful in the treatment of diseases in which neoangiogenesis is part ofthe overall pathology, e.g., diabetic retinal vascularization, as wellas various forms of cancer.

Cancers which are treatable in accordance with the present inventiondemonstrate high levels of gene and protein expression. Examples of suchcancers include cancers of the brain, genitourinary tract, lymphaticsystem, stomach, larynx and lung. These include histiocytic lymphoma,lung adenocarcinoma and small cell lung cancers. Additional examplesinclude cancers in which overexpression or activation of Raf-activatingoncogenes (e.g., K-ras, erb-B) is observed. More particularly, suchcancers include pancreatic and breast carcinoma.

SUMMARY OF THE INVENTION

A compound is disclosed in accordance with formula

or a pharmaceutically acceptable salt, hydrate or prodrug thereof,

wherein

R₁ is H, C₁₋₁₀ alkyl, C₃₋₆ cycloalkyl, C₅₋₁₀ aryl, halo, OH, C₃₋₁₀heterocyclyl, or C₅₋₁₀ heteroaryl; said alkyl, alkenyl, alkynyl, aryl,heteroaryl and heterocyclyl being optionally substituted with from oneto three members selected from R^(a);

R₂&R₃ are independently H, C₁₋₆ alkyl, C₅₋₁₀ aryl, C₃₋₆ cycloalkyl, OH,NO₂, —NH₂, or halogen;

R₄ is H, C₁₋₁₀ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₅₋₁₀ aryl, C₃₋₁₀ heterocyclyl, C₁₋₆ alkoxyNR₇R₈, NO₂, OH, —NH₂or C₅₋₁₀ heteroaryl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl andheterocyclyl being optionally substituted with from one to three membersselected from R^(a);

R₅ is H, or C₁₋₆ alkyl, OR, halo, NH₂ or NO₂;

R^(a) is H, C₁₋₁₀ alkyl halogen, NO₂, OR, —NR, NR₇R₈, R₇R₈, C₅₋₁₀ aryl,C₅₋₁₀ heteroaryl or C₃₋₁₀ heterocyclyl,

R is H, or C₁₋₆ alkyl; and

R₇&R₈ are independently H, C₁₋₁₀ alkyl, C₃₋₆ cycloalkyl, COR, COOR,COO—, C₅₋₁₀ aryl, C₃₋₁₀ heterocyclyl, or C₅₋₁₀ heteroaryl or NR₇R₈ canbe taken together to form a heterocyclic 5-10 membered saturated orunsaturated ring containing, in addition to the nitrogen atom, one totwo additional heteroatoms selected from the group consisting of N, Oand S.

Also disclosed is a pharmaceutical composition which is comprised of acompound represented by the formula I:

wherein R₁, R₂, R₃, R₄ and R₅ are described as above or apharmaceutically acceptable salt or hydrate or prodrug thereof incombination with a carrier.

Also included is a method of treating a tyrosine kinase dependentdisease or condition in a mammal which comprises administering to amammalian patient in need of such treatment a tyrosine kinase dependentdisease or condition treating amount of a compound of formula I or apharmaceutically acceptable salt, hydrate or pro-drug thereof.

Also included is a method of treating cancer in a mammalian patient inneed of such treatment which is comprised of administering to saidpatient an anti-cancer effective amount of a compound of formula I or apharmaceutically acceptable salt, hydrate or pro-drug thereof.

Also included in the present invention is a method of treating diseasesin which neoangiogenesis is implicated, which is comprised ofadministering to a mammalian patient in need of such treatment acompound of formula I or a pharmaceutically acceptable salt, hydrate orpro-drug thereof in an amount which is effective for reducingneoangiogenesis.

More particularly, a method of treating ocular disease in whichneoangiogenesis occurs is included herein, which is comprised ofadministering to a mammalian patient in need of such treatment acompound of formula I or a pharmaceutically acceptable salt hydrate orpro-drug thereof in an amount which is effective for treating saidocular disease

More particularly, a method of treating retinal vascularization isincluded herein, which is comprised of administering to a mammalianpatient in need of such treatment a compound of formula I or apharmaceutically acceptable salt, hydrate or pro-drug thereof in anamount which is effective for treating retinal vascularization. Diabeticretinopathy is an example of a disease in which neoangiogenesis orretinal vascularization is part of the overall disease etiology. Alsoincluded is a method of treating age-related macular degeneration.

These and other aspects of the invention will be apparent from theteachings contained herein.

DETAILED DESCRIPTION OF THE INVENTION

The invention is described herein in detail using the terms definedbelow unless otherwise specified.

The term “alkyl” refers to a monovalent alkane (hydrocarbon) derivedradical containing from 1 to 10 carbon atoms unless otherwise defined.It may be straight, branched or cyclic. Preferred straight or branchedalkyl groups include methyl, ethyl, propyl, isopropyl, butyl andt-butyl. Preferred cycloalkyl groups include cyclopropyl, cyclobutyl,cycloheptyl, cyclopentyl and cyclohexyl.

Alkyl also includes a straight or branched alkyl group which contains oris interrupted by a cycloalkylene portion. Examples include thefollowing:

wherein: x plus y=from 0-10; and w plus z=from 0-9.

The alkylene and monovalent alkyl portion(s) of the alkyl group can beattached at any available point of attachment to the cycloalkyleneportion.

When substituted alkyl is present, this refers to a straight, branchedor cyclic alkyl group as defined above, substituted with 1-3 groups ofR^(a), described herein.

The term “alkenyl” refers to a hydrocarbon radical straight, branched orcyclic containing from 2 to 10 carbon atoms and at least one carbon tocarbon double bond. Preferably one carbon to carbon double bond ispresent, and up to four non-aromatic (non-resonating) carbon-carbondouble bonds may be present. Preferred alkenyl groups include ethenyl,propenyl, butenyl and cyclohexenyl. As described above with respect toalkyl, the straight, branched or cyclic portion of the alkenyl group maycontain double bonds and may be substituted with one to three groups ofR^(a), when a substituted alkenyl group is provided.

The term “alkynyl” refers to a hydrocarbon radical straight, branched orcyclic, containing from 2 to 10 carbon atoms and at least one carbon tocarbon triple bond. Up to three carbon-carbon triple bonds may bepresent. Preferred alkynyl groups include ethynyl, propynyl and butynyl.As described above with respect to alkyl, the straight, branched orcyclic portion of the alkynyl group may contain triple bonds and may besubstituted with 1-3 groups of R^(a), when a substituted alkynyl groupis provided.

Aryl refers to 5-10 membered aromatic rings e.g., phenyl, substitutedphenyl and like groups as well as rings which are fused, e.g., naphthyland the like. Aryl thus contains at least one ring having at least 5atoms, with up to two such rings being present, containing up to 10atoms therein, with alternating (resonating) double bonds betweenadjacent carbon atoms. The preferred aryl groups are phenyl andnaphthyl. Aryl groups may likewise be substituted with 1-3 groups ofR^(a) as defined herein. Preferred substituted aryls include phenyl andnaphthyl substituted with one or two groups.

The term heterocycle, heteroaryl or heterocyclic, as used herein exceptwhere noted, represents a stable 5- to 7-membered mono- or bicyclic orstable 7- to 10-membered bicyclic heterocyclic ring system, any ring ofwhich may be saturated or unsaturated, and which consists of carbonatoms and from one to three heteroatoms selected from the groupconsisting of N, O and S, and wherein the nitrogen and sulfurheteroatoms may optionally be oxidized, and the nitrogen heteroatom mayoptionally be quaternized, and including any bicyclic group in which anyof the above-defined heterocyclic rings is fused to a benzene ring. Theheterocyclic ring may be attached at any heteroatom or carbon atom whichresults in the creation of a stable structure. The heterocycle,heteroaryl or heterocyclic may be substituted with 1-3 groups of R^(a).Examples of such heterocyclic elements include piperidinyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl,azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl,pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl,isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl,quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl,benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl,furyl, tetrahydrofuryl, tetrahydropyranyl, thiophenyl, imidazopyridinyl,tetrazolyl, triazinyl, thienyl, benzothienyl, thiamorpholinyl sulfoxide,thiamorpholinyl sulfone, and oxadiazolyl. The term “alkoxy” refers tothose groups of the designated length in either a straight or branchedconfiguration and if two or more carbon atoms in length, they mayinclude a double or a triple bond. Exemplary of such alkoxy groups aremethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiarybutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy allyloxy, propargyloxy,and the like.

The term “halogen” is intended to include the halogen atom fluorine,chlorine, bromine and iodine.

The term “prodrug” refers to compounds which are drug precursors which,following administration and absorption, release the drug in vivo viasome metabolic process. Exemplary prodrugs include acyl amides of theamino compounds of this invention such as amides of alkanoic(C₁₋₆)acids,amides of aryl acids (e.g., benzoic acid) and alkane(C₁₋₆)dioic acids.

Tyrosine kinase dependent diseases or conditions refers tohyperproliferative disorders which are initiated/maintained by aberranttyrosine kinase enzyme activity. Examples include psoriasis, cancer,immunoregulation (graft rejection), atherosclerosis, rheumatoidarthritis, angiogenesis (e.g. tumor growth, diabetic retinopathy), etc.

The compounds of the present invention are in accordance with formula I:

or a pharmaceutically acceptable salt, hydrate or prodrug thereof,

wherein

R₁ is H, C₁₋₁₀ alkyl, C₃₋₆ cycloalkyl, C₅₋₁₀ aryl, halo, OH, C₃₋₁₀heterocyclyl, or C₅₋₁₀ heteroaryl; said alkyl, alkenyl, alkynyl, aryl,heteroaryl and heterocyclyl being optionally substituted with from oneto three members selected from R^(a);

R₂&R₃ are independently H, C₁₋₆ alkyl, C₅₋₁₀ aryl, C₃₋₆ cycloalkyl, OH,NO₂, —NH₂, or halogen;

R₄ is H, C₁₋₁₀ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₅₋₁₀ aryl, C₃₋₁₀ heterocyclyl, C₁₋₆ alkoxyNR₇R₈, NO₂, OH, —NH₂or C₅₋₁₀ heteroaryl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl andheterocyclyl being optionally substituted with from one to three membersselected from R^(a);

R₅ is H, or C₁₋₆ alkyl, OR, halo, NH₂ or NO₂;

R^(a) is H, C₁₋₁₀ alkyl, halogen, NO₂, OR, —NR, NR₇R₈, R₇R₈, C₅₋₁₀ aryl,C₅₋₁₀ heteroaryl or C₃₋₁₀ heterocyclyl,

R is H, or C₁₋₆ alkyl; and R₇&R₈ are independently H, C₁₋₁₀ alkyl, C₃₋₆cycloalkyl, COR, COOR, COO—, C₅₋₁₀ aryl, C₃₋₁₀ heterocyclyl, or C₅₋₁₀heteroaryl or NR₇R₈ can be taken together to form a heterocyclic 5-10membered saturated or unsaturated ring containing, in addition to thenitrogen atom, one to two additional heteroatoms selected from the groupconsisting of N, O and S.

A preferred subset of compounds of the present invention is realizedwhen:

R₁ is H, C₁₋₁₀ alkyl, C₅₋₁₀ aryl, C₃₋₁₀ heterocyclyl, or C₅₋₁₀heteroaryl; said alkyl, aryl, heteroaryl and heterocyclyl beingoptionally substituted with from one to three members selected fromR^(a);

R₂&R₃ are independently H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, OH, or halogen;

R₄ is H, C₁₋₁₀ alkyl, C₃₋₆ cycloalkyl, C₅₋₁₀ aryl, C₅₋₁₀ heteroaryl,C₃₋₁₀ heterocyclyl, C₁₋₆ alkoxyNR₇R₈, NO₂, OH, —NH₂ or C₅₋₁₀ heteroaryl,said alkyl, aryl, heteroaryl and heterocyclyl being optionallysubstituted with from one to three members selected from R^(a); and allother variables are as described above.

Examples of the compounds of this invention are:

3-(4-fluorophenyl)-6-(4-pyridyl) pyrazolo(1,5-A)pyrimidine,

3-(3-chlorophenyl)-6-(4-pyridyl) pyrazolo(1,5-A)pyrimidine,

3-(3,4-methylenedioxypheny)-6-(4-pyridyl) pyrazolo(1,5-A)pyrimidine,

3-(phenyl)-6-(4-pyrimidyl) pyrazolo(1,5-A)pyrimidine,

3-(4-fluorophenyl)-6-(4-pyrimidyl) pyrazolo(1,5-A)pyrimidine,

3-(3-chlorophenyl)-6-(4-pyrimidyl) pyrazolo(1,5-A)pyrimidine,

3-(3-thienyl)-6-(4-pyrimidyl) pyrazolo(1,5-A)pyrimidine,

3-(3-acetamidophenyl)-6-(4-methylphenyl) pyrazolo(1,5-A)pyrimidine,

3-(3-thienyl)-6-(4-methylphenyl) pyrazolo(l,5-A)pyrimidine,

3-(phenyl)-6-(4-methoxyphenyl) pyrazolo(1,5-A)pyrimidine,

3-(3-acetamidophenyl)-6-(4-methoxyphenyl)pyrazolo(1,5-A)pyrimidine,

3-(3-thienyl)-6-(4-methoxyphenyl) pyrazolo(1,5-A)pyrimidine,

3-(phenyl)-6-(4-methoxyphenyl) pyrazolo(1,5-A)pyrimidine,

3-(4-pyridyl)-6-(4-methoxyphenyl) pyrazolo(1,5-A)pyrimidine,

3-(phenyl)-6-(4-chmorophenyl) pyrazolo(1,5-A)pyrimidine.

3-(4-pyridyl)-6-(4-chlorophenyl) pyrazolo(1,5-A)pyrimidine,

3-(phenyl)-6-(4-methylphenyl) pyrazolo(1,5-A)pyrimidine,

3-(4-pyridyl)-6-(4-methylphenyl) pyrazolo(1,5-A)pyrimidine,

3-(4phenyl)-6-(2-pyridyl) pyrazolo(1,5- A)pyrimidine,

3-(4-pyridyl)-6-(2-pyridyl) pyrazolo(1,5-A)pyrimidine,

3-(phenyl)-6-(4-pyrimidyl) pyrazolo(1,5-A)pyrimidine,

3-(4-pyridyl)-6-(4-pyrimidyl) pyrazolo(1,5-A)pyrimidine,

3-(phenyl)-6-(2-pyrazinyl) pyrazolo(1,5-A)pyrimidine,

3-(4-pyridyl)-6-(2-pyrazinyl) pyrazolo(1,5-A)pyrimidine,

3-(3-pyridyl)-6-(4-methoxyphenyl) pyrazolo(1,5-A)pyrimidine,

3-(phenyl)-6-(4-pyridyl) pyrazolo(1,5-A)pyrimidine,

3-(3-pyridyl)-6-(4-pyridyl) pyrazolo(1,5-A)pyrimidine,

3-(4 pyridyl)-6-(4-methoxyphenyl) pyrazolo(1,5-A)pyrimidine,

3-(3-thienyl)-6-(4-methoxyphenyl) pyrazolo(1,5-A)pyrimidine,

3-(3-thienyl)-6-(4-hydroxyphenyl)pyrazolo(1,5-A)pyrimidine,

3-(3-thienyl)-6-(4-(2-(4-morpholinyl)ethoxy)phenyl)pyrazolo(1,5-A)pyrimidine,

3-(3-thienyl)-6-(cyclohexyl)pyrazolo (1,5-A)pyrimidine,

3-(bromo)-6-(4-methoxyphenyl) pyrazolo(1,5-A)pyrimidine,

3-(bromo)-6-(4-pyrimidyl) pyrazolo(1,5-A)pyrimidine,

3-(phenyl)-6-(2-(3-carboxy)pyridyl) pyrazolo(1,5-A)pyrimidine, and

3-(3-thienyl)-6-(4-pyridyl) pyrazolo(1,5-A)pyrimidine.

Schemes 1-3 for preparing the novel compounds of this invention arepresented below. The examples which follow the schemes illustrate thecompounds that can be synthesized by Schemes 1-3, but Schemes 1-3 arenot limited by the compounds in the tables nor by any particularsubstituents employed in the schemes for illustrative purposes. Theexamples specifically illustrate the application of the followingschemes to specific compounds.

Generally, a method for the preparation of 3,6-diarylpyrazolo(1,5-A)pyrimidines comprises mixing a commercially availablemalondialdehyde compound (1), with commercially available aminopyrazole(2) in an alcohol, such as ethanol, methanol, isopropanol, butanol andthe like, said alcohol containing catalytic quantities of an acid, suchas acetic acid, to yield (3),

wherein Ar₁ and Ar₂, respectively, are R₄ and R₁, as described above.

Scheme 2 depicts a means for making 3,6-diarylpyrazolo(1,5-A)pyrimidines when the desired aminopyrazole is notcommercially available. In a like manner to that described in scheme 1compound (8) is obtained. Treatment of (8) with a boronic acidderivative in the presence of a palladium catalyst provides after workupthe desired material (9). AR₁ and Ar₂ are as described above.

Scheme 3 illustrates another method for the preparation of 3,7diarylpyrazolo(1,5-A)pyrimidines. The commercially available ketone (15)and nitrile (18) are treated seperately with dimethylformamidedimethylacetal (16) in refluxing toluene to give products (17) and (19)respectively. Compound (19) is then treated with hydrazinehydrochloridein refluxing ethanol to give the aminopyrazole (20). Compounds (17) and(20) and then treated with catalytic amounts of acetic acid in ethanolas described previously giving the desired of 3,7diarylpyrazolo(1,5-A)pyrimidines (21). AR₁ and Ar₂ are as describedabove.

The invention described herein includes a pharmaceutical compositionwhich is comprised of a compound of formula I or a pharmaceuticallyacceptable salt or hydrate thereof in combination with a carrier. Asused herein the terms “pharmaceutically acceptable salts” and “hydrates”refer to those salts and hydrated forms of the compound which would beapparent to the pharmaceutical chemist, i.e., those which favorablyaffect the physical or pharmacokinetic properties of the compound, suchas solubility, palatability, absorption, distribution, metabolism andexcretion. Other factors, more practical in nature, which are alsoimportant in the selection, are the cost of the raw materials, ease ofcrystallization, yield, stability, solubility, hygroscopicity andflowability of the resulting bulk drug.

When a compound of formula I is present as a salt or hydrate which isnon-pharmaceutically acceptable, this can be converted to a salt orhydrate form which is pharmaceutically acceptable in accordance with thepresent invention.

When the compound is negatively charged, it is balanced by a counterion,e.g., an alkali metal cation such as sodium or potassium. Other suitablecounterions include calcium, magnesium, zinc, ammonium, or alkylammoniumcations such as tetramethylammonium, tetrabutylammonium, choline,triethylhydroammonium, meglumine, triethanolhydroammonium, etc. Anappropriate number of counterions is associated with the molecule tomaintain overall charge neutrality. Likewise when the compound ispositively charged, e.g., protonated, an appropriate number ofnegatively charged counterions is present to maintain overall chargeneutrality.

Pharmaceutically acceptable salts also include acid addition salts.Thus, the compound can be used in the form of salts derived frominorganic or organic acids or bases. Examples include acetate, adipate,alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,citrate, camphorate, camphorsulfonate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate.Base salts include ammonium salts, alkali metal salts such as sodium andpotassium salts, alkaline earth metal salts such as calcium andmagnesium salts, salts with organic bases such as dicyclohexylaminesalts, N-methyl-D-glucamine, and salts with amino acids such asarginine, lysine, and so forth. Also, the basic nitrogen-containinggroups may be quaternized with such agents as lower alkyl halides, suchas methyl, ethyl, propyl, and butyl chloride, bromides and iodides;dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates,long chain halides such as decyl, lauryl, myristyl and stearylchlorides, bromides and iodides, aralkyl halides like benzyl andphenethyl bromides and others. Other pharmaceutically acceptable saltsinclude the sulfate salt ethanolate and sulfate salts.

The compounds of the present invention, may have asymmetric centers andoccur as racemates, racemic mixtures and as individual diastereomers, orenantiomers with all isomeric forms being included in the presentinvention. When any variable (e.g., aryl, heterocyle, R1, etc)occursmore than one time in any constituent or in Formula I, its definition oneach occcurence is independent of its definition at every otheroccurrence, unless otherwise stated.

The compounds of the invention can be formulated in a pharmaceuticalcomposition by combining the compound with a pharmaceutically acceptablecarrier. Examples of such compositions and carriers are set forth below.

The compounds may be employed in powder or crystalline form, in solutionor in suspension. They may be administered orally, parenterally(intravenously or intramuscularly), topically, transdermally or byinhalation.

Thus, the carrier employed may be, for example, either a solid orliquid. Examples of solid carriers include lactose, terra alba, sucrose,talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acidand the like. Examples of liquid carriers include syrup, peanut oil,olive oil, water and the like. Similarly, the carrier for oral use mayinclude time delay material well known in the art, such as glycerylmonostearate or glyceryl distearate alone or with a wax.

Topical applications may be formulated in carriers such as hydrophobicor hydrophilic bases to form ointments, creams, lotions, in aqueous,oleaginous or alcoholic liquids to form paints or in dry diluents toform powders. Such topical formulations can be used to treat oculardiseases as well as inflammatory diseases such as rheumatoid arthritis,psoriasis, contact dermatitis, delayed hypersensitivity reactions andthe like.

Examples of oral solid dosage forms include tablets, capsules, troches,lozenges and the like. The size of the dosage form will vary widely, butpreferably will be from about 25 mg to about 500 mg. Examples of oralliquid dosage forms include solutions, suspensions, syrups, emulsions,soft gelatin capsules and the like. Examples of injectable dosage formsinclude sterile injectable liquids, e.g., solutions, emulsions andsuspensions. Examples of injectable solids would include powders whichare reconstituted, dissolved or suspended in a liquid prior toinjection.

In injectable compositions, the carrier is typically comprised ofsterile water, saline or another injectable liquid, e.g., peanut oil forintramuscular injections. Also, various buffering agents, preservativesand the like can be included.

For the methods of treatment disclosed herein, dosages can be varieddepending upon the overall condition of the patient, the nature of theillness being treated and other factors. An example of a suitable oraldosage range is from about 0.1 to about 80 mg/kg per day, in single ordivided doses. An example of a suitable parenteral dosage range is fromabout 0.1 to about 80 mg/kg per day, in single or divided dosages,administered by intravenous or intramuscular injection. An example of atopical dosage range is from about 0.1 mg to about 150 mg, appliedexternally from about one to four times a day. An example of aninhalation dosage range is from about 0.01 mg/kg to about 1 mg/kg perday.

The compounds may be administered in conventional dosages as a singleagent or in combination with other therapeutically active compounds.

EXAMPLE 1

3-(4 pyridyl)-6-(4-methoxyphenyl) pyrazolo(1,5-A)pyrimidine

A solution of commercially available dialdehyde (4, 12.9 mg, 0.0724mmol) and aminopyrazole (5, 10.4 mg 0.0652mmol) in ethanol was heated at80° C. for 10 hours in a test tube containing catalytic amounts ofacetic acid. The reaction was cooled to room temperature and the yellowsolid was collected by filtration and the title compound was washed withcold ethanol and dried (11.7 mg, 60%). Mass Spec (M+1, 303).

EXAMPLE 2

3-(3-thienyl)-6-(4-methoxyphenyl) pyrazolo(1,5-A)pyrimidine

Step 1.

A solution of 4 (713 mg, 4.0 mmol) and commercially availaible 7 (648mg, 4.0 mmol), discussed above in ethanol (20 mL) was heated at 75° C.for 4 h. The resulting white suspension was as decribed in example 1 for4 hours, then cooled to 20° C., filtered, and washed with methanol (3×5mL) to provide 10 as a white powder (1.07 g, 88%, mp=168-170° C.): ¹HNMR (CDCl₃) δ 8.79 (d, 1 H, J=2.2 Hz), 8.74 (d, 1 H, J=2.2 Hz), 8.12 (s,1 H), 7.51 (d, 2 H, J=8.8 Hz), 7.05 (d, 2 H, J=8.8 Hz), 3.88 (s, 3 H).

Step 2.

A suspension of (10) (250 mg, 0.82 mmol), thiophene-3-boronic acid (11)(158 mg, 1.24 mmol), and aqueous sodium carbonate (2 M, 1 mL) in dioxane(5 mL) was de-gassed by evacuating and backflushing with argon (3×).

Tetrakis(triphenyl-phosphine) palladium (20 mg, 0.017 mmol) was addedand the reaction mixture was de-gassed again. The argon filled flask wasthen submerged in an oil bath pre-heated to 90° C. and was heated atthat temperature for 16 h. After cooling to 20° C., the yellowprecipitate which formed was collected by filtration and was washed withmethanol (3×5 mL) to provide the title compound as a yellow powder (220mg, 87%, mp=191-193° C.): ¹H NMR (CDCl₃) δ 8.79 (d, 1 H, J=2.4 Hz), 8.76(d, 1 H, J=2.2 Hz), 8.37 (s, 1 H), 7.90 (dd, 1 H, J=2.9, 1.3 Hz), 7.70(dd, 1 H, J=4.9, 1.2 Hz), 7.54 (d, 2 H, J=8.8 Hz), 7.43 (d, 1 H, J=4.9,2.9 Hz), 7.06 (d, 2 H, J=8.8 Hz), 3.88 (s, 3H).

EXAMPLE 3

3-(3-thienyl)-6-(4-hydroxyphenyl)pyrazolo(1,5-A)pyrimidine Ethanethiol(30 mg, 36 uL) was added dropwise over 1 min to a suspension of sodiumhydride (23 mg, 0.98 mmol) in dry DMF (2 mL) under argon. After 15 min,the compound of example 2 (50 mg, 0.16 mmol) was added and the reactionmixture was heated at 150° C. for 1.5 h. The resulting brown solutionwas cooled, poured into water (25 mL) and washed with ethyl acetate(2×25 mL). The combined organics were dried (Na₂SO₄), concentrated, andpurified by flash chromatography (40% EtOAc/Hexanes) to give the titlecompound as a yellow solid [11 mg, 23%, R_(f)=0.12 (40% EtOAc/Hexanes)]:¹H NMR (CD₃OD) δ 8.96 (d, 1 H, J=2.4 Hz), 8.85 (d, 1 H, J=2.2 Hz), 8.44(s, 1 H), 7.94 (dd, 1 H, J=2.9, 1.2 Hz), 7.74 (dd, 1 H, J=4.9, 1.2 Hz),7.56 (d, 2 H, J=8.8 Hz), 7.46 (dd, 1 H, J=4.9, 2.9 Hz), 6.94 (d, 2H,J=8.6Hz).

EXAMPLE 4

3-(3-thienyl)-6-(4-(2-(4-morpholinyl)ethoxy)phenyl)pyrazolo(1,5-A)pyrimidine

A solution of example 3 (11 mg, 0.038 mmol), cesium carbonate (37 mg,0.11 mmol), N-(2-chloroethyl)morpholine hydrochloride (7 mg, 0.11 mmol),and sodium iodide (0.013 mmol) in DMF (3 mL) was heated at 60° C. underargon for 16 h. The reaction mixture was then poured into water (25 mL)and washed with ethyl acetate (2×25 mL). The combined organics weredried (Na₂SO₄), concentrated, and purified by flash chromatography [50%Hexanes/CHCl₃(NH₃)] to give the title compound as a yellow solid [10 mg,65%, mp=149-151° C., R_(f)=0.39 (100% CHCl₃(NH₃))]: ¹H NMR (CDCl₃) δ8.77 (d, 1 H, J=2.2 Hz), 8.75 (d, 1 H, J=2.2 Hz), 8.36 (s, 1 H), 7.90(dd, 1 H, J=2.9, 1.3 Hz), 7.69 (dd, 1 H, J=4.9, 1.3 Hz), 7.52 (d, 2 H,J=8.8 Hz), 7.43 (d, 1 H, J=4.9, 2.9 Hz), 7.06 (d, 2 H, J=8.8 Hz), 4.18(t, 2H,J=5.7Hz),3.76(t, 4H,J=4.6Hz), 2.85 (t, 2H,J=5.7 Hz), 2.61 (t, 4H, J=4.6 Hz); FAB MS (M⁺+1) Anal Calcd. for C₂₂H₂₂N₄O₂S : C, 65.00; H,5.46; N, 13.78. Found C, 64.98; H, 5.55; N, 14.02.

EXAMPLE 5

3-(3-thiophenyl)-7-(4-pyridyl) pyrazolo(1,5-A)pyrimidine

A 13×100 mm reaction tube was charged with aminopyrazole (22) (16.5 mg,0.100 mmol) dissolved in 0.500 mL EtOH and vinylogous amide (23) (17.6mg, 0.100 mmol) dissolved in 0.200 mL EtOH. Glacial acetic acid (1 drop)was added and the reaction was heated to 80° C. for 14 h. An additional0.100 mL of glacial acetic acid was added and heating was continued foran additional 6 h. The sample was concentrated to dryness to provide thedesired title compound. Analysis by mass spectrometry showed[M+H]⁺279.2.

EXAMPLE 6

3-(3-thienyl)-6-(cyclohexyl) pyrazolo(1,5-A)pyrimidine

Step 1

Palladium on carbon (10%, 2 g) was added to a solution of 24 (5.62 g,23.4 mmol) in ethanol (100 mL) under an argon atmosphere. Afterevacuating and backflushing the reaction vessel with H₂ (3×), the blacksuspension was stirred vigorously under an H₂ filled balloon for 16 h.The reaction mixture was then filtered through celite, washed with ethylacetate (200 mL) and concentrated to provide 25 as a colorless oil (5.0g, 88%): ¹H NMR (CDCl₃) d 4.18 (q, 4 H, J=7.1 Hz), 3.13 (d, 1 H, J=9.2Hz), 2.08 (m, 1 H), 1.73-1.56 (m, 5 H), 1.35-1.01 (m, 5 H), 1.26(t, 6 H,J=7.0Hz).

Step 2

A solution of 25 (2.0 g, 8.3 mmol) in dry THF (30 mL) at 0° C. wastreated with lithium aluminum hydride (1.0 M in THF, 16.5 mL, 16.5 mmol)over a 5 min period. The reaction mixture was warmed gradually to 15° C.over 20 min and then was re-cooled to 0° C. and quenched sequentiallywith water (630 uL), aqueous sodium hydroxide (1 N, 630 uL), and thenwater (3×630 uL). The resulting white suspension was stirred for 15 min,dried (Na₂SO₄), and filtered washing with THF (100 mL) and ethyl acetate(100 mL). The filtrate was concentrated to provide 26 as a white solid(1.35 g, 100%): ¹H NMR (CDCl₃) d 3.83 (ddd, 4 H), 1.77-1.62 (m, 5 H),1.57 (m, 1 H), 1.42 (m, 1 H), 1.30-0.96 (m, 5 H).

Step 3

A solution of oxalyl chloride (2.39 g, 1.64 mL, 18.8 mmol) in CH₂Cl₂ (50mL) at −60° C. was treated with DMSO (2.94 g, 2.67 mL, 37.6 mmol) inCH₂Cl₂ (10 mL) over 2 min. After 5 min, a solution of 26 (1.35 g, 8.5mmol) in CH₂Cl₂ (20 mL) was added and the resulting suspension wasmaintained at −60° C. for 15 min. Triethylamine (8.6 g, 11.8 mL, 85mmol) was then added and the reaction mixture was allowed to warm to 20°C. The quenched reaction was poured into water (200 mL) and washed withCH₂Cl₂ (2×100 mL). The combined organics were dried (Na₂SO₄),concentrated, and purified by flash chromatography (40% Hexane/EtOAc) toprovide 27 as a viscous oil [135 mg, 10%, R_(f)=0.34 (40%Hexane/EtOAc)]: ¹H NMR (CDCl₃) d 8.26 (s, 2 H), 2.09 (tt, 1 H),1.85-1.68 (m, 6 H), 1.39-1.13 (m, 5 H).

Step 4

A solution of 27 (50 mg, 0.30 mmol) and 22 (47 mg, 0.30 mmol) in ethanol(5 mL) was heated at 75° C. for 16 h. After cooling, the reactionmixture was concentrated, and the crude product was purified by flashchromatography (25% EtOAc/Hexane) to provide 6 as a yellow solid [54 mg,63%, R_(f)=0.33 (25% EtOAc/Hexanes)]: ¹H NMR (CDCl₃) d 8.48 (d, 1 H,J=2.2 Hz), 8.44 (d, 1 H, J=1.5 Hz), 8.30 (s, 1 H), 7.86 (dd, 1 H, J=2.9,1.1 Hz), 7.66 (dd, 1 H, J=4.9, 1.2 Hz), 7.41 (dd, 1 H, J=4.9, 2.9 Hz),2.64 (m, 1 H), 2.03-1.80 (m, 5 H), 1.52-1.27 (m, 5 H); FAB MS (M⁺+1)calcd. for 284, found 284; Anal Calcd. for C₁₆H₁₇N₃S (0.05 H₂O): C,67.59; H, 6.06; N, 14.78. Found C, 67.66; H, 6.12; N, 15.14.

Kinase inhibition is demonstrated in accordance with the followingprotocol.

VEGF RECEPTOR KINASE ASSAY

VEGF receptor kinase activity is measured by incorporation ofradio-labeled phosphate into polyglutamic acid, tyrosine, 4:1 (pEY)substrate. The phosphorylated pEY product is trapped onto a filtermembrane and the incoporation of radio-labeled phosphate quantified byscintillation counting.

MATERIALS

VEGF Receptor Kinase The intracellular tyrosine kinase domains of humanKDR (Terman, B.I. et al. Oncogene (1991) vol. 6, pp. 1677-1683.) andFlT-1 (Shibuya, M. et al. Oncogene (1990) vol. 5, pp. 519-524) werecloned as glutathione S-transferase (GST) gene fusion proteins. This wasaccomplished by cloning the cytoplasmic domain of the KDR kinase as anin frame fusion at the carboxy terminus of the GST gene. Solublerecombinant GST-kinase domain fusion proteins were expressed inSpodoptera frugiperda (Sf21) insect cells (Invitrogen) using abaculovirus expression vector (pAcG2T, Pharmingen).

Lysis Buffer

50 mM Tris pH 7.4, 0.5 M NaCl, 5 mM DTT, 1 mM EDTA, 0.5% triton X-100,10% glycerol, 10 mg/ml of each leupeptin, pepstatin and aprotinin and 1mM phenylmethylsulfonyl fluoride (all Sigma).

Wash Buffer

50 mM Tris pH 7.4,0.5 M NaCl, 5 mM DTT, 1 mM EDTA, 0.05% triton X-100,10% glycerol, 10 mg/ml of each leupeptin, pepstatin and aprotinin and 1mM phenylmethylsulfonyl fluoride.

Dialysis Buffer

50 mM Tris pH 7.4, 0.5 M NaCl, 5 mM DTT, 1 mM EDTA, 0.05% triton X-100,50% glycerol, 10 mg/ml of each leupeptin, pepstatin and aprotinin and 1mM phenylmethylsuflonyl fluoride

10× reaction buffer

200 mM Tris, pH 7.4, 1.0 M NaCl, 50 mM MnCl₂, 10 mM DTT and 5 mg/mlbovine serum albumin (Sigma).

Enzyme Dilution Buffer

50 mM Tris, pH 7.4, 0.1 M NaCl, 1 mM DTT, 10% glycerol, 100 mg/ml BSA.

10× Substrate

750 μg/ml poly (glutamic acid, tyrosine; 4:1) (Sigma).

Stop Solution

30% trichloroacetic acid, 0.2 M sodium pyrophosphate (both Fisher).

Wash Solution

15% trichloroacetic acid, 0.2 M sodium pyrophosphate.

Filter Plates

Millipore #MAFC NOB, GF/C glass fiber 96 well plate.

METHOD

A. Protein Purification

1. Sf21 cells were infected with recombinant virus at a multiplicity ofinfection of 5 virus particles/cell and grown at 27 ° C. for 48 hours.

2. All steps were performed at 4° C. Infected cells were harvested bycentrifugation at 1000× g and lysed at 4° C. for 30 minutes with{fraction (1/10)} volume of lysis buffer followed by centrifugation at100,000× g for 1 hour. The supernatant was then passed over aglutathione Sepharose column (Pharmacia) equilibrated in lysis bufferand washed with 5 volumes of the same buffer followed by 5 volumes ofwash buffer. Recombinant GST-KDR protein was eluted with wash buffer/ 10mM reduced glutathione (Sigma) and dialyzed against dialysis buffer.

B. VEGF Receptor Kinase Assay

1. Add 5 μl of inhibitor or control to the assay in 50% DMSO.

2. Add 35 μl of reaction mix containing 5 μl of 10× reaction buffer, 5μl 25 mM ATP/10 μCi [³³P]ATP (Amersham), and 5 μl 10× substrate.

3. Start the reaction by the addition of 10 μl of KDR (25 nM) in enzymedilution buffer.

4. Mix and incubate at room temperature for 15 minutes.

5. Stop by the addition of 50 μl stop solution.

6. Incubate for 15 minutes at 4° C.

7. Transfer a 90 μl aliquot to filter plate.

8. Aspirate and wash 3 times with wash solution.

9. Add 30 μl of scintillation cocktail, seal plate and count in a WallacMicrobeta scintillation counter.

Human Umbilical Vein Endothelial Cell Mitogenesis Assay

Expression of VEGF receptors that mediate mitogenic responses to thegrowth factor is largely restricted to vascular endothelial cells. Humanumbilical vein endothelial cells (HUVECs) in culture proliferate inresponse to VEGF treatment and can be used as an assay system toquantify the effects of KDR kinase inhibitors on VEGF stimulation. Inthe assay described, quiescent HUVEC monolayers are treated with vehicleor test compound 2 hours prior to addition of VEGF or basic fibroblastgrowth factor (bFGF). The mitogenic response to VEGF or bFGF isdetermined by measuring the incorporation of [³H]thymidine into cellularDNA.

Materials

HUVECs

HUVECs frozen as primary culture isolates are obtained from CloneticsCorp. Cells are maintained in Endothelial Growth Medium (EGM; Clonetics)and are used for mitogenic assays at passages 3-7.

Culture Plates

NUNCLON 96-well polystyrene tissue culture plates (NUNC #167008).

Assay Medium

Dulbecco's modification of Eagle's medium containing 1 g/ml glucose(low-glucose DMEM; Mediatech) plus 10% (v/v) fetal bovine serum(Clonetics).

Test Compounds

Working stocks of test compounds are diluted serially in 100%dimethylsulfoxide (DMSO) to 400-fold greater than their desired finalconcentrations. Final dilutions to 1× concentration are made directlyinto Assay Medium immediately prior to addition to cells.

10× Growth Factors

Solutions of human VEGF₁₆₅ (500 ng/ml; R&D Systems) and bFGF (10 ng/ml;R&D Systems) are prepared in Assay Medium.

10× [³H]Thymidine

[Methyl-³H]Thymidine (20 Ci/mmol; Dupont-NEN) is diluted to 80 uCi/mi inlow-glucose DMEM.

Cell Wash Medium

Hank's balanced salt solution (Mediatech) containing 1 mg/ml bovineserum albumin (Boehringer-Mannheim).

Cell Lysis Solution

1 N NaOH, 2% (w/v) Na₂CO₃.

Method

1. HUVEC monolayers maintained in EGM are harvested by trypsinizationand plated at a density of 4000 cells per 100 ul Assay Medium per wellin 96-well plates. Cells are growth-arrested for 24 hours at 37° C. in ahumidified atmosphere containing 5% CO₂.

2. Growth-arrest medium is replaced by 100 ul Assay Medium containingeither vehicle (0.25% [v/v] DMSO) or the desired final concentration oftest compound. All determinations are performed in triplicate. Cells arethen incubated at 37° C./5% CO₂ for 2 hours to allow test compounds toenter cells.

3. After the 2-hour pretreatment period, cells are stimulated byaddition of 10 ul/well of either Assay Medium, 10× VEGF solution or 10×bFGF solution. Cells are then incubated at 37° C./5% CO₂.

4. After 24 hours in the presence of growth factors, 10× [³H]Thymidine(10 ul/well) is added.

5. Three days after addition of [³H]thymidine, medium is removed byaspiration, and cells are washed twice with Cell Wash Medium (400ul/well followed by 200 ul/well). The washed, adherent cells are thensolubilized by addition of Cell Lysis Solution (100 ul/well) and warmingto 37° C. for 30 minutes. Cell lysates are transferred to 7-ml glassscintillation vials containing 150 ul of water. Scintillation cocktail(5 ml/vial) is added, and cell-associated radioactivity is determined byliquid scintillation spectroscopy.

Based upon the foregoing assays the compounds of formula I areinhibitors of VEGF and thus are useful for the inhibition ofneoangiogenesis, such as in the treatment of occular disease, e.g.,diabetic retinopathy and in the treatment of cancers, e.g., solidtumors. The instant compounds inhibit VEGF-stimulated mitogenesis ofhuman vascular endothelial cells in culture with IC₅₀ values between150-650 nM. These compounds also show selectivity over related tyrosinekinases (e.g. FGFR1 and the Src family).

What is claimed is:
 1. A compound in accordance with formula I:

or a pharmaceutically acceptable salt, hydrate or prodrug thereof,wherein R₁ is aryl, optionally substituted with one to threesubstituents selected from R^(a); R₂ and R₃ are independently H, C₁₋₆alkyl, aryl, C₃₋₆ cycloalkyl, OH, NO₂, NH₂, or halogen; R₄ is aryl orheteroaryl, substituted with one to three substituents selected fromR^(a); R₅ is H, or C₁₋₆ alkyl, OR, halo, NH₂ or NO₂; R^(a) is C₁₋₁₀alkyl, halogen, NO₂, OR, OC₁₋₆ alkyl-NR₇R₈, NR₇R₈, aryl, orheterocyclyl; R is H or C₁₋₆ alkyl; and R₇ and R₈ are independentlyselected from: H, C₁₋₁₀ alkyl, C₃₋₆ cycloalkyl, COR, COOR, aryl, andheterocyclyl, or NR₇R₈ can be taken together to form a heterocyclic 5-10membered saturated or unsaturated ring optionally containing, inaddition to the nitrogen atom, one to two additional heteroatomsselected from N, O and S.
 2. A compound in accordance with claim 1 whichis: 3-(4-fluorophenyl)-6-(4-pyridyl) pyrazolo(1,5-A)pyrimidine,3-(3-chlorophenyl)-6-(4-pyridyl) pyrazolo(1,5-A)pyrimidine,3-(3,4-methylenedioxyphenyl)-6-(4-pyridyl) pyrazolo(1,5-A)pyrimidine,3-(phenyl)-6-(4-pyrimidyl) pyrazolo(1,5-A)pyrimidine,3-(4-fluorophenyl)-6-(4-pyrimidyl) pyrazolo(1,5-A)pyrimidine,3-(3-chlorophenyl)-6-(4-pyrimidyl) pyrazolo(1,5-A)pyrimidine,3-(3-acetamidophenyl)-6-(4-methylphenyl) pyrazolo(1,5-A)pyrimidine,3-(phenyl)-6-(4-methoxyphenyl) pyrazolo(1,5-A)pyrimidine,3-(3-acetamidophenyl)-6-(4-methoxyphenyl)pyrazolo(1,5-A)pyrimidine,3-(phenyl)-6-(4-methoxyphenyl) pyrazolo(1,5-A)pyrimidine,3-(phenyl)-6-(4-chlorophenyl) pyrazolo(1,5-A)pyrimidine,3-(phenyl)-6-(4-methylphenyl) pyrazolo(1,5-A)pyrimidine,3-(phenyl)-6-(2-pyridyl) pyrazolo(1,5-A)pyrimidine,3-(phenyl)-6-(4-pyrimidyl) pyrazolo(1,5-A)pyrimidine,3-(phenyl)-6-(2-pyrazinyl) pyrazolo(1,5-A)pyrimidine,3-(phenyl)-6-(4-pyridyl) pyrazolo(1,5-A)pyrimidine, or3-(phenyl)-6-(2-(3-carboxy)pyridyl) pyrazolo(1,5-A)pyrimidine; or apharmaceutically acceptable salt thereof.
 3. A pharmaceuticalcomposition which is comprised of a compound in accordance with claim 1or a pharmaceutically acceptable salt, prodrug or hydrate thereof incombination with a carrier.
 4. A method of trea ting cancer in amammalian p atient in need of such treatment which is comprised ofadministering to said patient a therapeutically effective amount of acompound of claim 1 or a pharmaceutically acceptable salt, prodrug orhydrate thereof.
 5. A method of treating cancer in accordance with claim4 wherein the cancer is selected from cancers of the brain,genitourinary tract, lymphatic system, stomach, larynx and lung.
 6. Amethod in accordance with claim 4 wherein the cancer is selected fromhistiocytic lymphoma, lung adenocarcinoma, small cell lung cancers,pancreatic cancer, glioblastomas and breast carcinoma.
 7. A method oftreating a disease in which neoangiogenesis is implicated, which iscomprised of administering to a mammalian patient in need of suchtreatment a therapeutically effective amount of a compound of claim 1 ora pharmaceutically acceptable salt, prodrug or hydrate thereof.
 8. Amethod in accordance with claim 7 wherein the disease is an oculardisease.
 9. A method of treating retinal vascularization which iscomprised of administering to a mammalian patient in need of suchtreatment a therapeutically effective amount of a compound of claim 1 ora pharmaceutically acceptable salt, prodrug or hydrate thereof.
 10. Amethod of treating diabetic retinopathy which is comprised ofadministering to a mammalian patient in need of such treatment atherapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt, prodrug or hydrate thereof.
 11. Amethod of treating age-related macular degeneration which is comprisedof administering to a mammalian patient in need of such treatment atherapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt, prodrug or hydrate thereof.
 12. Amethod of treating inflammatory diseases which is comprised ofadministering to a mammalian patient in need of such treatment atherapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt, prodrug or hydrate thereof.
 13. Amethod according to claim 12 wherein the inflammatory disease isselected from rheumatoid arthritis, psoriasis, contact dermatitis anddelayed hypersensitivity reactions.
 14. A method of inhibiting tyrosinekinase which is comprised of administering to a mammalian patient inneed of such treatment a therapeutically effective amount of a compoundof claim 1 or a pharmaceutically acceptable salt, prodrug or hydratethereof.